On February 13, 2023 MacroGenics, Inc. (NASDAQ: MGNX), a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported preliminary safety and anti-tumor activity data from the dose expansion phase of the Company’s ongoing Phase 1 clinical trial of lorigerlimab, a bispecific, tetravalent PD-1 × CTLA-4 DART molecule (Press release, MacroGenics, FEB 13, 2023, View Source [SID1234627105]). This investigational molecule was designed to block PD-1 with enhanced CTLA-4 blockade on dual PD-1/CTLA-4-expressing cells, such as tumor-infiltrating lymphocytes (TILs), while maintaining maximal PD-1 blockade on all PD-1-expressing cells. The preliminary data is being presented in a poster titled "Lorigerlimab, a Bispecific PD-1 × CTLA-4 DART Molecule in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase 1 Expansion Cohort" (Poster #155) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO-GU) Cancers Symposium taking place February 16-18, 2023, in San Francisco, CA.

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Cohort Expansion Results Update

The ASCO (Free ASCO Whitepaper)-GU abstract included data as of September 10, 2022; updated data as of a December 12, 2022 cut-off are included below and will be presented at ASCO (Free ASCO Whitepaper)-GU.

As of the December 12, 2022 data cut-off, 118 patients with mCRPC, melanoma, non-small cell lung cancer or microsatellite-stable colorectal cancer were enrolled in the cohort expansion phase of the lorigerlimab Phase 1 study at the dose of 6.0 mg/kg, administered intravenously every three weeks (Q3W). Confirmed objective responses were observed across the histology-specific cohorts; preliminary efficacy results for mCRPC are presented in the poster and below.

Preliminary Safety Results

The safety analysis is based on 127 patients who received lorigerlimab at a dose of 6 mg/kg Q3W, including 118 enrolled in the four dose expansion cohorts plus nine patients from dose escalation. Median exposure was 14.4 weeks (range: 1.9 – 100.1 weeks) with a median of four infusions administered per patient. Twenty-four patients remained on lorigerlimab as of the December 12, 2022 data cut-off; 103 discontinued for the following reasons: progressive disease (PD) (n=66), adverse events (AE) (n=31), patient/physician decision (n=5), or death due to PD (n=1).

The results demonstrated a manageable overall safety profile. Treatment-related AEs (TRAEs) occurred in 86.6% of patients, with the most common among them (≥15%) being fatigue, rash, pruritus, hypothyroidism, and pyrexia. Rates of grade ≥3 TRAEs and immune-related AEs were 34.6% and 7.9%, respectively. AEs resulted in treatment discontinuation in 24.4% of patients. There were no fatal AEs related to lorigerlimab.

Preliminary Anti-tumor Activity in mCRPC Cohort

As of the December 12, 2022 data cut-off, 42 patients had been enrolled in the mCRPC expansion cohort. Patients had previously received a median of two prior therapies (range: 1 – 9) for advanced disease, with 35 patients (83.3%) having received docetaxel and 34 patients (81.0%) having received androgen receptor antagonist therapy. The median exposure to lorigerlimab was 19.2 weeks (range: 3.3 – 55.1 weeks), with a median of five infusions administered per patient.

A total of 35 patients with mCRPC had measurable soft tissue disease per RECIST v1.1 at study entry. Nine of the 35 patients (25.7%) achieved confirmed partial responses (cPR). The median duration of response for these nine patients was 4.6 months (range: 2.8 – 8.6+ months), with four patients remaining on lorigerlimab as of data cut-off. Among the other five patients who had achieved cPR, four discontinued due to unrelated adverse events, and one patient discontinued due to physician decision.

Reductions in PSA levels of ≥ 50% were observed in 12 of 42 patients (28.6%), and 9 of the 12 maintained PSA50 response ≥ 3 months. Nine of 42 patients (21.4%), including the nine who achieved cPR, had reductions in their PSA levels of ≥ 90% as of the data cut-off.

"To date, checkpoint inhibition has not fared well in the treatment of patients with late-stage mCRPC. Previously, anti-CTLA-4 therapy, whether alone or in combination with an anti-PD-1 agent, resulted in increased risk for immune-related toxicity with very modest anti-tumor activity," said Scott Koenig, M.D., Ph.D., President and CEO of MacroGenics. "We designed lorigerlimab to have preferential blockade on dual PD-1/CTLA-4-expressing cells such as TILs, which are most abundant in the tumor microenvironment. As part of this study, biomarker analyses indicated that lorigerlimab was shown to induce T-cell activation as evidenced by an increased frequency of circulating Ki67+ and ICOS+ T cells. We believe we are seeing the benefit of lorigerlimab’s design and are very encouraged by this latest data set from our ongoing Phase 1 study. Looking forward, we plan to initiate a Phase 2 study of lorigerlimab in patients with mCRPC later this year and anticipate providing an update on the proposed study later this quarter."

ASCO-GU Poster Presentation

MacroGenics’ lorigerlimab poster presentation will be available for on-demand viewing on the ASCO (Free ASCO Whitepaper)-GU website and on the "Events & Presentations" page on MacroGenics’ website at View Source

About Lorigerlimab

Lorigerlimab (previously known as MGD019) is an investigational, bispecific IgG4-based, Fc-bearing DART molecule that was designed to enhance blockade on PD-1 and CTLA-4 dual-expressing, tumor-infiltrating lymphocytes, while maintaining maximal PD-1 blockade on all circulating PD-1-expressing cells. In addition to the study described above and presented in the poster, MacroGenics is also evaluating the activity of lorigerlimab in combination with vobramitamab duocarmazine (previously known as MGC018, an investigational B7-H3-directed antibody-drug conjugate) in a study in patients with advanced solid tumors.